Cardiac hypertrophy is the common adaptive stress-response of the heart to multiple mechanical or biochemical stimuli. Although initially compensatory, hypertrophy ultimately decompensates leading to the syndrome of congestive heart failure. A single critical transducer of hypertrophy/heart failure has not been identified, and probably does not exist. Rather, cardiac hypertrophy and failure are the culmination has not been identified, and probably does not exist. Rather, cardiac hypertrophy and failure are the culmination of various stimuli activating multiple signaling cascades, each of which modify the end response. In determining the mechanisms for hypertrophy progression to heart failure we hypothesize that the molecular and cellular consequences of adaptive hypertrophy ultimately cause its decompensation and transition to heart failure. The five Projects of this SCoR renewal each examine different, but inter-related aspects of the putative integrated hypertrophy signaling pathways. Dr. Dorns' project uses a novel approach of PKC isoform- specific activation and inhibition to delineate the roles of different PKCs in cardiac adaptation. Project 2 will continue its highly successful survey of beta1 and beta2 adrenergic receptor polymorphisms in heart failure, and further define the influence of receptor variants on cardiac physiology, and the response to beta blockade. Dr. Molkentins' Project investigates a novel hypertrophy signaling pathway, calcineurin/NFAT-3, to determine its role in cardiac adaptation and maladaptation. Project 4 examines the function of sarcoplasmic calcium cycling proteins in normal and failing mouse hearts and characterizes naturally occurring human genetic polymorphisms of phospholamban and the sarcoplasmic reticulum calcium ATPase. Project 5 will examine the notion that cardiac hypertrophy leads to heart failure in part due to an increase in the relative expression of beta versus alpha myosin heavy chain. Each of the Projects takes advantage of studies performed in cultured cells, transgenic mice or rabbits and humans, and are supported by a Mouse Physiology Core which provides a physiological modeling and hemodynamic analysis, and a Clinical Core which provides information and physiological assessment of cardiac function of heart failure patients, and collects human myocardial specimens for molecular and biochemical assays proposed in all the Projects. We believe this thematically linked, multi-disciplinary research program will continue to break new ground in increasing our understanding of the pathogenesis and optimal management of human heart failure.